Pulmonary and sinus fungal diseases in non-

immunocompromised patients

David W. Denning FRCP 1,2 and Arunaloke Chakrabarti MD 3

1Global Action Fund for Fungal Infections,

2The National Aspergillosis Centre, University Hospital of South Manchester, The

University of Manchester, Manchester Academic Health Science Centre, Manchester,

UK

3Department of Medical Microbiology, Postgraduate Institute of Medical Education &

Research, Chandigarh 160012, India

Corresponding author:

Professor David Denning FRCP FRCPath FMedSci

The National Aspergillosis Centre

University Hospital of South Manchester, the University of Manchester,

Manchester Academic Health Science Centre,

Manchester, UK

E-mail: ddenning@manchester.ac.uk

Total number of words of the manuscript: 4300 words

Abstract: 198 words.

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Abstract

The human respiratory tract is exposed daily to airborne fungi, fungal enzymes

and secondary metabolites. The endemic fungi Histoplasma capsulatum,

Coccidioides spp., Blastomyces dermatitidis and Paracoccidioides brasiliensis, and

occasionally Aspergillus fumigatus, are primary pulmonary pathogens of

otherwise healthy people. The majority resolve such infections, few develop

disease. However, many fungi are directly allergenic by colonizing the

respiratory tract, or indirectly through contact with cell wall constituents and

proteases, causing or exacerbating allergic disease. Increasing evidence

implicates high indoor fungal exposures as a precipitant of asthma in children,

and in worsening asthma symptoms. Lung or airways infection by endemic fungi

or Aspergillus can be diagnosed with respiratory sample culture or serum IgG

antibody testing. Sputum, induced sputum or bronchial specimens are all

suitable specimens for detecting fungi; microscopy, culture, galactomannan

antigen and Aspergillus PCR are useful tests. Antifungal treatment is indicated in

almost all patients with chronic cavitary pulmonary infections, chronic invasive

and granulomatous rhinosinusitis and Aspergillus bronchitis. The majority of

patients with fungal asthma benefit from antifungal therapy. Adverse reactions

to oral azoles, drug interactions and azole resistance in Aspergillus spp. limit

therapy. Environmental exposures, genetic and structural pulmonary risk factors

probably underlie disease, but are poorly understood.

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Introduction

Different species of fungi may be inhaled; some are capable of surviving at body

temperature and evading healthy host defenses. A very small number of

pathogenic fungi causing pulmonary infection are true pathogens, notably those

causing the endemic mycoses – Coccidioides spp, Histoplasma spp., Blastomyces

dermatitidis, Paracoccidioides brasiliensis1. Others, such as Aspergillus spp. and

Cryptococcus spp. can overwhelm innate defenses when inhaled in substantial

quantities or patients can have specific defects in innate immunity what we

currently consider ‘normal’ defenses. Most of these subtle defense ‘holes’ are

poorly understood.

We review here the common upper and lower airway fungal diseases in non-

immunocompromised hosts – their frequency, the clinical and radiological

presentation, the mode of diagnosis and current therapy. Rare manifestations of

these infections are not addressed in any depth. We also describe some less well

understood issues, notably the presentation of fungal exposure in buildings or

through occupation. Treatment is addressed in a summary format only –

additional expert advice and in depth literature should be consulted.

Search strategy

We searched Medline and our own extensive article archives for relevant

material. The limit of 100 references has been maintained. There is no attempt to

formalize this review as any type of meta-analysis or other scoping/systematic

review, because of the breadth of subjects covered.

Fungal rhinosinusitis

Fungal rhinosinusitis (FRS) is now recognized more frequently, and somewhat

controversially separated into different phenotypes. Therapy varies by

phenotypes. As ~10% of the adult population suffers from chronic

rhinosinusitis2, and a small minority of these by FRS of different types, many

millions are affected3. A dysfunctional interplay between the human host and

fungi at the nasal and sinus mucosa results in a wide clinical spectrum of FRS3.

FRS can be classified into four broad clinical presentations4:

a) Immunocompromised – acute invasive phenotype with fulminant course.

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b) Mild or no discernable impairment of immunity – chronic invasive or

granulomatous phenotype with chronic course

c) Colonization of nasal passage and sinus – fungal ball phenotype with

chronic course

d) Atopic or genetic susceptible host – eosinophil-related FRS including

allergic fungal rhinosinusitis (AFRS) with chronic or occasionally acute

course.

Fungi can be present on nasal mucosa of any healthy person and invade the

mucous membrane in the first two types only5.

Chronic invasive or granulomatous FRS: It is not clear whether the two entities

are separate or different presentations of same phenotype. Chronic invasive FRS

is seen worldwide in patients with diabetes or on steroid therapy, whereas the

granulomatous type is seen in apparently healthy people in a geographically

restricted region extending from Sudan to India. Abundant hyphae with mixed

inflammation and isolation of Aspergillus fumigatus are hallmarks of chronic

invasive FRS4,6. Rarely dematiaceous fungi including Alternaria and Curvularia

spp. are isolated. In granulomatous FRS, A. flavus is more common and hyphae

are sparse in tissue and usually present inside giant cells. Both diseases have a

chronic course with marked orbital involvement. Diagnosis is established by

histopathology of endoscopically removed samples, and culture. Aspergillus IgG

antibodies or precipitins may be useful in monitoring therapy7. Management

consists of surgical debridement, preferably endoscopically, and antifungal

therapy. Amphotericin B, itraconazole or voriconazole for 6-12 weeks are

effective post-debridement 8-10.

Fungal ball: Fungi colonize the sinus mucosa and produce dense conglomeration

of hyphae in one sinus cavity, most commonly the maxillary sinus, occasionally a

sphenoid sinus6. The disease occurs worldwide but is prevalent in older women

in southern France11,12. Management consists of endoscopic removal4. Antifungal

therapy is not required for maxillary fungal ball, but may be advisable post-

operatively in those with sphenoid sinus disease13.

AFRS: Akin to allergic bronchopulmonary aspergillosis (ABPA), a profound Th2

response with eosinophilic mucin in the sinus is the hallmark of AFRS14. The

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disease is prevalent in arid and tropical region of the world. In north India, a high

rate of 110 AFRS patients per 100,000 population is documented especially

during the wheat-thrashing season (March-April)15. In Israel, a very high rate,

500/100,000, has been also described16. AFRS and ABPA may co-exist in the

same patient17.

Patients present with symptoms of chronic sinusitis, which may include facial

pressure, headache, nasal stuffiness, discharge18. Often there is a history of

multiple surgeries and incomplete responses to antibacterial therapy; AFRS

should be suspected in intractable sinusitis with nasal polyposis. Some patients

present with proptosis. CT scanning of the sinuses reveals opacification with

concretions and/or calcifications. Positive type I hypersensitivity is usual and the

presence of eosinophilic mucin containing fungal hyphae is diagnostic.

Dematiaceous fungi including Alternaria, Bipolaris, Curvularia are commonly

isolated from patients in western world. In contrast, A. flavus is isolated from

patients in south Asia, middle east and Sudan.

The cornerstones of management are removal of nasal polyps combined with

topical corticosteroids immediately post-operatively, short term antibiotic

therapy for concurrent bacterial infection (notably Staphylococcus aureus)19 and

nasal irrigation with saline. Relapse is common, and prevented in part by longer

term nasal steroids and saline20,21. In double-blind placebo-controlled studies,

there was limited benefit to local and systemic antifungal agents22-24; the benefit

is in relapsing cases25-27. Some patients benefit from a salicylate-free diet28.

Community acquired Aspergillus pneumonia

Massive exposures to Aspergillus conidia can overwhelm the innate immunity of

lung and acute disease follow (Figure 1)29,30. Lower levels of exposure following

influenza, prior lung disease, notably chronic obstructive pulmonary disease

(COPD), and corticosteroid therapy also predispose patients to community

acquired Aspergillus pneumonia31-33. An acute or subacute onset is typical. On

chest imaging a miliary, bilateral diffuse pattern or unilateral upper lobe cavitary

disease is seen. Aspergillus spp. may be isolated from respiratory tract specimens

and galactomannan is detectable on bronchoscopy fluid. Aspergillus IgG

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antibodies become detectable, but the time course is uncertain. Outcome is poor

in those with concurrent viral infection and also given corticosteroids32.

Complete resolution or development of chronic pulmonary aspergillosis (CPA)

occurs in other patients. Antifungal therapy is advised, with corticosteroids in

bilateral diffuse disease, but data are scant.

Chronic pulmonary aspergillosis

Chronic pulmonary aspergillosis (CPA) is a challenging disorder, complicating

several respiratory diseases34. The global estimate of burden is at ~3 million, of

whom about 1.2 million have had pulmonary tuberculosis 35-37. These patients are

not immunocompromised but have prior or current lung defects (Table 1)37.

By convention, CPA has been present for at least 3 months38. Slow progression

over time is common. Patients with CPA are commonly middle-aged men (60%)

with long standing constitutional symptoms of profound fatigue and weight loss,

pulmonary symptoms of productive cough, haemoptysis of variable degree, chest

discomfort and shortness of breath. Imaging, reveals one or more small or large,

thick or thin-walled cavities with or without an aspergilloma (most common), or

solid or cavitating nodules39 (Table 2), or rarely a large mass lesion or extensive

consolidation with limited air spaces (figure 2). Pleural thickening is

characteristic, but not universal. Aspergillomas are conglomerates of fungal

hyphae as biofilm within pulmonary cavities. Patients often have recurrent

infections with Streptococcus pneumonia or Haemophilus influenzae. Differential

diagnosis includes the other fungal entities discussed in this article, as well as

tuberculosis, non-tuberculous mycobacterial infection and lung carcinoma.

Subacute invasive pulmonary aspergillosis (previously chronic necrotizing

pulmonary aspergillosis) develops over 4-12 weeks usually in moderately

immunocompromised patients, which should be managed as invasive

aspergillosis40,41.

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The key diagnostic test for CPA is Aspergillus IgG antibody (or the less sensitive

precipitins), which is detectable in >90% of patients with cavitary disease42 but

about 60% of those with Aspergillus nodules. Inflammatory markers are raised in

almost all patients. Positive PCR or culture of Aspergillus or galactomannan from

respiratory samples is supportive evidence40,43, if the radiological findings are

typical. Some patients have raised total IgE or Aspergillus specific IgE, but may

not have asthma or ABPA.

Simple aspergillomas should be resected, if possible, preferably via video-

assisted thoracic surgery technique (table 3)40,41,44. Surgery may be required for

more complex patients with haemoptysis, un-responsive unilateral disease

and/or azole resistance. Each patient should be carefully risk assessed as

summarized by Farid et al44.

Long term oral antifungal therapy is recommended for most patients (Table

3)40,41. The objectives of therapy are to minimize symptoms45, notably cough,

sputum production, fatigue, weight and reduce the risk of haemoptysis.

Antifungal therapy does not improve breathlessness appreciably, unless they are

very deconditioned, and can exercise more; pulmonary rehabilitation may be

helpful. Patients with resected Aspergillus nodules and those with minimal

symptoms and no radiological progression over several months, need follow up,

without therapy.

Haemoptysis may be controlled with tranexamic acid and bronchial artery

embolization, rarely surgical resection, and may be a sign of therapeutic failure

and/or antifungal resistance. Acquired azole resistance may occur during

prolonged therapy, especially in those with low serum concentrations of azole, or

poor compliance and high burdens of infection. Currently such patients may have

to resort to intermittent or long term intravenous therapy.40

Pulmonary histoplasmosis

Histoplasmosis has 3 main pulmonary manifestations – acute disease after major

exposure to Histoplasma capsulatum (especially following cave exploration) and

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chronic cavitary diseases in immunocompetent people and disseminated disease

in the immunocompromised (Figure 1). Most exposures are sub-clinical leaving

small calcified granulomata in the lungs or spleen.

Acute pulmonary histoplasmosis follows a few days after a point exposure. The

diagnosis is usually made clinically, with consolidation on chest radiograph58.

Serological diagnosis is either or both of Histoplasma antigen or antibody,

especially antibody seroconversion59.

The annual number of new, symptomless infections can only be estimated by

skin test conversion, a rarely undertaken procedure, and varies substantially by

geography. For example in Mexico, the positive skin test rate varied from 11.2 to

–56.2 million of the estimated 112 million population60. Primary infection, with

or without symptoms appears to confer some immunity to re-infection, unless

profoundly immunocompromised.

Chronic cavitary pulmonary histoplasmosis is uncommon. Most frequently seen

in those with emphysema, ‘cavitation’ may represent focal areas of consolidation

surrounding bullae, initially58,61. It is usually bilateral, involving the upper lobes.

Patients present with productive cough, increasing shortness of breath, weight

loss, night sweats and sometimes fever over many months or years. Gradually

expanding cavities are seen on chest radiographs, progressing to local fibrosis61.

Respiratory samples usually yield a positive culture for H. capsulatum and IgG

antibody in >90% of patients62. The laboratory should be warned of the

possibility of Histoplasma as it is a class 3 pathogen. Long term itraconazole

therapy is advised (Table 3)46,47. Fibrosing mediastinitis and airway-obstructing

lymphadenopathy are rare complications, typically without concurrent

pulmonary disease.

Pulmonary coccidioidomycosis

Coccidioidomycosis is caused by Coccidioides immitis or Coccidioides posadasii

found in the environment in south-western USA, northern Mexico and pockets in

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Central and South America1. In the USA, about 60% of cases occur in Arizona, but

sporadic imported cases are reported across the world. Infection follows

inhalation of one or more arthroconidia.

Infection is asymptomatic in ~60%1. However, primary infection, often referred

to as ‘Valley Fever’ presents as flu-like symptoms including fever, chest pain,

cough or weight loss, sometimes associated with erythema nodosum or

erythema multiforme (Figure 1). Discrete nodules in the lower lobes, or

consolidation may be seen63. Sometimes primary pulmonary coccidioidomycosis

is severe with a prolonged, debilitating course. About 90% of patients have

detectable IgM antibody within 2 weeks of illness. Primary coccidioidomycosis

resolves or progresses to chronic and progressive pulmonary disease or

disseminates causing meningitis, skin, bone or lymph node disease.

Chronic pulmonary coccidioidomycosis presents with persistent cough, weight

loss and malaise. Usually there is a single, thin-walled cavity, but patients may

have enlarging or multiplying nodules or cavities63. Cavitary pulmonary disease

usually yields a positive sputum or BAL culture64.

A specific manifestation of coccidioidomycosis is the pulmonary nodule, with is

usually single, asymptomatic and benign (Table 2). Radiologically they do not

resemble carcinoma63, but in non-endemic areas are usually removed because

only histological confirmation minimises anxiety about the diagnosis.

The laboratory should be cautioned as Coccidioides spp. are classified class 3

pathogens. The fungus is white on agar and produces infectious arthroconidia,

rectangular microscopic structures. In tissue only spherules are seen - large,

thick walled circular structures containing endospores. The complement fixation

(CF) test for IgG antibodies is the usual means of establishing the diagnosis of

chronic pulmonary coccidioidomycosis as the titer correlates with the severity of

disease64, falling with successful therapy.

Primary coccidioidomycosis, is usually treated symptomatically; itraconazole or

fluconazole may shorten the duration of disease, but do not impact on relapse49.

Pulmonary nodules do not require antifungal therapy48. Chronic cavitary

pulmonary coccidioidomycosis requires prolonged therapy (Table 3)48, and

relapse is reported even after a year of therapy. There are no convincing data

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supporting the use of any one azole over another; echinocandins are ineffective.

Severe disease is treated with amphotericin B48,50. Relapse is more likely if the CF

antibody titer is >1:256. If relapse occurs, long term azole therapy is appropriate.

Pulmonary paracoccidioidomycosis

Paracoccidioidomycosis occurs in certain areas of Central and South America.

About 3,500 new cases occur in Brazil each year65. The dimorphic fungus

Paracoccidioides brasiliensis is acquired through inhalation. Initial infection is

usually subclinical; ill-understood factors or immunosuppression allow

reactivation.

A rare manifestation of paracoccidioidomycosis in those younger than 30 years

is acute, progressive infection (Figure 1) known as the 'juvenile' form,

characterized in the lung by adenopathy, unilateral pleural effusion and miliary-

like shadows51. Disseminated infection to other organs is typical. Untreated cases

may be fatal.

Chronic pulmonary paracoccidioidomycosis51 is often associated with disease in

other organs, notably the skin and mouth, lymph nodes, spleen, liver, adrenal

glands. Pulmonary lesions are granulomatous nodules that often cavitate but

rarely calcify. Co-existent pulmonary tuberculosis is frequent. Itraconazole is

superior to trimethoprim- sulphamethoxazole (Table 3)52.

Pulmonary blastomycosis

Pulmonary blastomycosis is usually seen with cutaneous blastomycosis. Almost

all cases occur in N. America, with rare cases reported from Africa and India. The

most common presentation is with cough, weight loss, chest pain, skin lesions,

fever and occasionally hemoptysis (Figure 1)53. Primary pulmonary

blastomycosis may be asymptomatic or present as acute or subacute pneumonia,

ranging from mild to severe. Itraconazole therapy is curative (Table 3).

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Cryptococcal pneumonia

Pulmonary cryptococcosis is rare, but probably underdiagnosed and more

common in immunocompromised patients (Figure 1). It is most often caused by

Cryptococcus neoformans var. grubii (worldwide) or C. gattii (geographically

restricted). C. gattii is found in eucalyptus and other large tropical trees in

tropical and sub-tropical regions expanding to include Australia, Asia, Europe

and the Pacific Northwest.

Patients may be asymptomatic and present with an abnormal chest radiograph66.

The most common symptoms are cough which is usually productive and

occasionally hemoptysis. Single or multiple peripheral nodules, sometimes in

association with areas of consolidation, are common, but occasionally pleural

effusion and consolidation are seen. Airways colonisation also occurs67. C. gattii

pulmonary infection includes multifocal areas of consolidation, both solid and

cavitary nodules, pleural effusion and endobronchial lesions. Hypoxemia is rare.

Patients may have disseminated disease with meningitis or a cerebral

cryptococcoma.

CT-guided or VATS lung biopsy or resection is the commonest means of

establishing the diagnosis. Culture from respiratory samples is often negative but

cryptococcal antigen is occasionally detected in serum (or CSF)67. Most patients

with C. gattii are not immunocompromised but may have ill-defined immune

deficits. If not resected, antifungal therapy with fluconazole is advised, unless

meningitis is also present (Table 3)54.

Fungal asthma

Current evidence links a proportion of asthma cases to fungi in two ways. First,

significant indoor dampness, mould odour and visible mould exposure can

trigger asthma, with an increased risk of 30-50%68. Second, many asthma

patients demonstrate sensitization to several fungi including Aspergillus,

Alternaria and Cladosporium and this is usually linked to worse asthma control69.

The latter is often referred to as ‘fungal asthma’54. Fungal sensitization is

common in severe asthma, at 33% or higher frequency70. Genetic factors

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probably play role in fungal asthma54,. Severe airway inflammation and multiple

hospital admissions are common70-72.

The clinical spectrum of fungal asthma is wide and includes ABPA 72. Fungal

asthma can manifest as fungal sensitization or fungal allergy. Fungal

sensitization is an exaggerated immune response to a fungus, without

inflammation or tissue damage, clinically documented by an elevated fungal-

specific IgE while fungal allergy is an immune-mediated inflammatory response

to a fungus causing tissue damage. Although many fungi can cause sensitization,

fungal allergy is predominantly due to thermotolerant fungi especially

Aspergillus fumigatus. ABPA is the most well characterized form of fungal

asthma72. Severe asthma with fungal sensitization (SAFS) denotes a phenotype of

severe asthma characterized by severe asthma and fungal sensitization but

exclusion of ABPA69.

ABPA presents as poorly controlled asthma, with exacerbations consisting of

increased amounts of sputum, with mucous plugs, together with malaise and

weight loss 72. Chest imaging may reveal mucous plugging, and, in later stages,

central bronchiectasis. Hyper-attentuated mucus is visible in a substantial

proportion of patients in India, and uncommon in elsewhere, for unclear reasons.

The diagnosis of various forms of fungal asthma is made on a combination of

clinical, radiological and immunological findings. A positive A. fumigatus specific

IgE is required for an ABPA diagnosis. A raised total IgE of >1,000 IU/L

arbitrarily distinguishes ABPA from SAFS55,72.

Management of fungal asthma includes inhaled and/or oral corticosteroids,

immunisation against S. pneumonia and H. influenzae, management of excess

mucus with therapeutic bronchoscopy (if severe plugging) and hypertonic saline

nebulisers and azithromycin as an airway anti-inflammatory agent55,56. Oral or

inhaled antifungal therapy is beneficial for the majority of patients, if tolerated

(Table 3). Complications of ABPA include bronchiectasis and pulmonary fibrosis

(including chronic pulmonary aspergillosis)56.

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Thunderstorm asthma: Thunderstorm asthma refers to an association between

high fungal spore counts, thunderstorms and severe asthma attacks73. Increased

humidity and high winds trigger increased spore release and dissemination.

Several fungi have been implicated including Didymella exitialis, Sporobolomyces

and Alternaria74 as well as grass allergens. Affected patients may be so ill as to

require ICU admission. It is not clear if there is a role for antifungal therapy.

Occupational asthma: There are a few cases described of occupational asthma

attributable to fungi. Examples include mushroom workers with positive IgE and

IgG to Pleurotus cornucopiae75., condom manufacturers where Lycopodium

clavatum was used as a dusting agent, a research microbiologist with asthma and

with specific IgE antibodies to Dictyostelium discoideum, a coal miner who

developed occupational asthma with specific IgE antibodies to Rhizopus

nigricans, following mine contamination with this fungus, coffee grinders and

plywood factory workers with specific IgE to Neurospora species and orchid

growers with sensitivity to Cryptostroma corticale, found in the bark chips used

in cultivating the orchids.

Aspergillus bronchitis

Aspergillus bronchitis is a chronic superficial infection of the lower airways,

characteristically in non-immunocompromised patients57,76. It may be caused by

any of the pathogenic species of Aspergillus. The majority of patients have

bronchiectasis or cystic fibrosis (CF). Approximately 10,000 adults with CF and

Aspergillus bronchitis are estimated worldwide77, but no estimate of the non-CF

burden has been made. The commonest clinical presentations in non-CF patients

are either chronic productive cough with tenacious mucus production and

dyspnoea or recurrent exacerbations of pre-existing airway disease with

incomplete response to antibiotics57. Mucous impaction requiring therapeutic

bronchoscopy is an occasional, dramatic presentation.

As Aspergilli may colonise the respiratory tree, the combination of symptoms

with microbiological demonstration of Aspergillus in the airways at least twice is

required for diagnosis57. Some patients have airway ulceration or membrane

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formation, some with obstructing, thick mucus, and microscopy and either

galactomannan or PCR is sufficient for diagnosis. Some patients have an elevated

Aspergillus IgG antibody test.

Oral azole therapy for ~4 months is effective in most patients (Table 3).

However, relapse is frequent and some patients need long term therapy.

Cystic fibrosis

Patients with cystic fibrosis may acquire fungi in their sputum, commonly

Candida spp, which is of limited import, A. fumigatus which may represent ABPA,

Aspergillus bronchitis or transient colonisation, Exophiala dermatiditis of

uncertain importance and Scedosporium spp78.. Those patients with Aspergillus in

their airways have a slightly more rapid decline in their lung function than those

without79. Infection of the airways is manifest as Aspergillus bronchitis and ABPA,

but many patients are not affected, or only sensitised to A. fumigatus80. The

optimal management of fungal infection and allergy in CF is uncertain.

Mouldy building exposure and building sickness syndrome

Poor quality buildings, water leaks and inadequate ventilation may lead to excess

fungal growth inside a building. In addition to precipitating or worsening

asthma, some patients develop other symptoms, dubbed ‘Building Sickness

Syndrome’ (BSS)81. Other names for this collection of syndromes include ‘Sick

Building Syndrome’ and Sick House Syndrome’ or the evocative ‘Toxic Black

Mould’, and may include patients with chemical intolerance (multiple chemical

sensitivity)82-85. As many of the symptoms are non-specific and there is no

diagnostic test available, the diagnosis rests on a careful history of the patient’s

symptoms and environmental exposures, and exclusion of other causes of

common symptoms such as fatigue83-85. A diagrammatic summary of the multiple

causes of BSS is shown in Figure S1.

Clinical clues to a positive diagnosis of BSS related to fungal or mould exposure

include three elements:

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An exposure history of visible mould or smell, usually with improvement

after leaving the building,

Eye, nose or throat irritation and hoarseness combined with difficulty in

concentration and sensitivity to odours is characteristic of exposure to

volatile organic compounds (VOCs),

Headache, dizziness, nausea, dry skin or pruritus, nasal stuffiness,

lethargy are common and sometimes weight loss and muscle pains,

Exacerbation or initiation of allergic rhinitis or asthma.

In addition to a empathetic ear and eradication of dampness and mould from the

house or office, patients need to be thoroughly examined, checked for alternative

diagnoses with an initial screen of inflammatory markers, anaemia, liver, renal

and thyroid abnormality and have a chest radiograph. Co-morbidity, especially

psychological, is common86. If allergic or pulmonary symptoms are prominent

then testing for fungal sensitisation and/or IgG testing is appropriate. Preferably

this should be combined with a careful evaluation of the home or workplace, by

an experienced professional, measuring fungal exposure. The Quick

Environmental Exposure and Sensitivity Inventory questionnaire may be

valuable in assessing patients87.

The cornerstone of management is avoidance. Repair of leaks, reduction in

condensation, and improvement in ventilation are key to clinical improvement.

Patients with evidence of chemical intolerance need advice on avoidance, which

can be challenging and may find cognitive behavioural therapy helpful88. No

evidence basis exists for any particular therapeutic strategy, partly because of

the highly individual nature of the exposures.

Extrinsic allergic alveolitis and other symptoms caused by fungi

Extrinsic allergic alveolitis (EAA) caused by fungi is well described (table S1)89,90.

Some cases of EAA follow complex microbial exposures, such as ‘grain fever’ or

‘organic dust syndrome’ which includes fungal material. Confirmation of a causal

relationship with any specific agent can be defined by a provocation test, often

difficult to undertake.

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As fungal exposure may be unobtrusive, EAA caused by fungi is probably more

common than realized. A well documented example was an outbreak of

pulmonary symptoms in several workers producing citric acid from Aspergillus

niger who had skin-prick positivity to Aspergillus91. Other examples include malt

workers’ lung92, tobacco workers lung93, bakers94 and stipatosis95. Many

individual case examples have not been given disease monikers yet, and so table

S1 is certainly incomplete. Many occupational exposures lead to pulmonary

symptoms, which do not fulfill criteria for asthma or EAA75,96.

There are no data published as to whether antifungal therapy is of any value for

either EAA or occupational asthma related to fungi. Some patients present late

with interstitial lung disease or pulmonary fibrosis. Generally, avoidance is

recommended, but for some patients this has significant economic consequences.

A trial of itraconazole may be worthwhile, as a corticosteroid-sparing agent, and

if subtle exposure continues and is unavoidable.

Conclusion

Airborne fungi cause a wide spectrum of lung and upper and lower airways

disease, some acute and others indolent or chronic. High exposure is a common

factor. Underlying lung or airway disease is a common antecedent factor, and the

course of fungal disease is highly variable – probably attributable to local airway

and lung defenses and genetic factors, which are not well understood. The

majority of infectious syndromes and some allergic manifestations improve with

antifungal therapy.

Author contributions: Both authors contributed equally to writing of this paper

Funding source: None

Potential conflicts of interest: DWD holds Founder shares in F2G Ltd a University of Manchester spin-out antifungal discovery company, in Novocyt which markets the Myconostica real-time molecular assays and has current grant support from the National Institute of Health Research, Medical Research Council, Global Action Fund for Fungal Infections and the Fungal Infection Trust. He acts or has recently acted as a consultant to Astellas, Sigma Tau, Basilea, Scynexis, Cidara, Biosergen Biosergen and Pulmocide. In the last 3 years, he has been paid for talks on behalf of Astellas,

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2526272829303132333435

Dynamiker, Gilead, Merck and Pfizer. He is also a member of the Infectious Disease Society of America Aspergillosis Guidelines and European Society for Clinical Microbiology and Infectious Diseases Aspergillosis Guidelines groups. AC has no conflict of interest, working full time in an Indian government sponsored autonomous medical institute.

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References

1. Vallabhaneni S, Mody RK, Walker T, Chiller T. The global burden of fungal

diseases. Infect Dis Clin North Am 2016;30:1-11.

2. Hamilos DL. Chronic rhinosinusitis: epidemiology and medical

management. J Allergy Clin Immunol. 2011; 128:693–707.

3. Lam K, Schleimer R, Kern RC. The etiology and pathogenesis of chronic

rhinosinusitis: a review of current hypotheses. Curr Allergy Asthma Rep

2015;15:41.

4. Chakrabarti A, Denning DW, Ferguson BJ, et al. Fungal rhinosinusitis: a

categorization and definitional schema addressing current controversies.

Laryngoscope. 2009;119:1809-18.

5. Porter PC, Lim DJ, Maskatia ZK, et al. Airway surface mycosis in chronic

TH2-associated airway disease. J Allergy Clin Immunol 2014;134:325-31.

6. Hope WW, Walsh TJ, Denning DW. The invasive and saprophytic

syndromes due to Aspergillus spp. Med Mycol 2005;43 (Suppl 1):S207-38.

7. Talwar P, Sharma M, Sehgal SC, Ghose KK. Serology of Aspergillus

granuloma. Mycopathologia 1982;79:79-85.

8. Halderman A, Shrestha R, Sindwani R. Chronic granulomatous invasive

fungal sinusitis: an evolving approach to management. Int Forum Allergy Rhinol

2014;4:280-3

9. Callejas CA, Douglas RG. Fungal rhinosinusitis: what every allergist should

know. Clin Exp Allergy 2013;43:835-49.

10. Gumaa SA, Mahgoub ES, Hay RJ. Post-operative responses of paranasal

Aspergillus granuloma to itraconazole. Trans R Soc Trop Med Hyg 1992; 86:93–4.

11. Klossek JM, Serrano E, Péloquin L, Percodani J, Fontanel JP, Pessey JJ.

Functional endoscopic sinus surgery and 109 mycetomas of paranasal sinuses.

Laryngoscope 1997;107:112-7.

12. Grosjean P, Weber R. Fungus balls of the paranasal sinuses: a review. Eur

Arch Otorhinolaryngol 2007;264:461-70.

13. Devèze A, Facon F, Latil G, Moulin G, Payan-Cassin H, Dessi P. Cavernous

sinus thrombosis secondary to non-invasive sphenoid aspergillosis. Rhinology

2005;43:152-5.

18

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

14. Taylor MJ, Ponikau JU, Sherris DA, et al. Detection of fungal organisms in

eosinophilic mucin using a fluorescein-labeled chitin-specific binding protein.

Otolaryngol Head Neck Surg 2002;127:377-83.

15. Chakrabarti A, Rudramurthy SM, Panda N, Das A, Singh A. Epidemiology of

chronic fungal rhinosinusitis in rural India. Mycoses 2015;58:294-302.

16. Ben-Ami R, Denning DW. Estimating the burden of fungal diseases in

Israel. Israel Med Assc J 2015;17:374-9.

17. Pamkabo C, Shah A. Allergic Aspergillus sinusitis and its association with

allergic bronchopulmonary aspergillosis. Asia Pac Allergy 2011;1:130-7.

18. Hox V, Maes T, Huvenne W, et al. A chest physician's guide to mechanisms

of sinonasal disease. Thorax 2015;70:353-8

19. Dutre T, Al Dousary S, Zhang N, Bachert C. Allergic fungal rhinosinusitis-

more than a fungal disease? J Allergy Clin Immunol 2013;132:487-9.

20. Kim ST, Sung UH, Jung JH, et al. The effect of maxillary sinus irrigation on

early prognostic factors after endoscopic sinus surgery: a preliminary study. Am

J Rhinol Allergy 2013;27:e158-61.

21. Pundir V, Pundir J, Lancaster G, et al. Role of corticosteroids in functional

endoscopic sinus surgery--a systematic review and meta-analysis. Rhinology

2016;54:3-19.

22. Orlandi RR,Marple BF, Georgelas A et al. Immunologic response to fungus

is not universally associated with rhinosinusitis. Otolaryngol–Head Neck Surg :

Off J Am Acad Otolaryngol- Head Neck Surg 2009; 141:750-756.

23. Ebbens FA, Scadding GK, Badia L, et al. Amphotericin B nasal lavages: not

a solution for patients with chronic rhinosinusitis. J Allergy Clin Immunol

2006;118:1149–56.

24. Ebbens FA, Fokkens WJ. The mold conundrum in chronic rhinosinusitis:

where do we stand today? Curr Allergy Asthma Rep 2008;8:93–101.

25. Hashemi M, Fereidani A, Berjis N, Okhovat SA, Eshaghain A. Effectiveness

of itraconazole on clinical symptoms and radiologic findings in patients with

recurrent chronic rhinosinusitis and nasal polyposis. Adv Biomed Res

2014;3:162.

26. Thanasumpun T, Batra PS. Oral antifungal therapy for chronic

rhinosinusitis

19

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

and its subtypes: a systematic review. Int Forum Allergy Rhinol 2011;1:382-9.

27. Chan KO, Genoway KA, Javer AR. Effectiveness of itraconazole in the

management of refractory allergic fungal rhinosinusitis. J Otolaryngol Head Neck

Surg 2008;37:870-4.

28. Sommer DD, Rotenberg BW, Sowerby LJ, et al. A novel treatment adjunct

for aspirin exacerbated respiratory disease: the low-salicylate diet: a multicenter

randomized control crossover trial. Int Forum Allergy Rhinol 2016;6:385-9.

29. http://www.aspergillus.org.uk/content/community-acquired-

aspergillus-pneumonia-andor-pneumonitis

30. Siddiqui S, Anderson VL, Hilligoss DM, et al. Fulminant mulch

pneumonitis: an emergency presentation of chronic granulomatous disease. Clin

Infect Dis 2007;45:673-681.

31. Clancy CJ, Nguyen MH. Acute community-acquired pneumonia due

to Aspergillus in presumably immunocompetent hosts: clues for recognition of a

rare but fatal disease. Chest 1998;114: 629-634.

32. Alshabani K, Haq A, Miyakawa R, Palla M, Soubani AO. Invasive pulmonary

aspergillosis in patients with influenza infection: report of two cases and

systematic review of the literature. Expert Rev Respir Med 2015;9:89-96.

33. Crum-Cianflone NF. Invasive aspergillosis associated with severe

influenza infections. Open Forum Infect Dis 2016;3:ofw171.

34. Kosmidis C, Denning DW. The clinical spectrum of pulmonary

aspergillosis. Thorax 2015;70:270-277.

35. Denning DW, Pleuvry A, Cole DC. Global burden of chronic pulmonary

aspergillosis as a sequel to tuberculosis. Bull WHO 2011;89:864-72.

36. Global Action Fund for Fungal Infections. ’95-95 by 2025’ Improving

outcomes for patients with fungal infections across the world: A Roadmap for the

next decade. May 2015. http://www.gaffi.org/roadmap/

37. Smith N, Denning DW. Underlying pulmonary disease frequency in

patients with chronic pulmonary aspergillosis. Eur Resp J 2011;37:865-72.

38. Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary

and fibrosing pulmonary and pleural aspergillosis: Case series, proposed

nomenclature and review. Clin Infect Dis 2003;37 (Suppl 3):S265-80.

20

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

39. Muldoon EG, Sharman A, Page ID, Bishop P, Denning DW. Aspergillus

nodules; another presentation of chronic pulmonary aspergillosis. BMC Pulm

Med 2016; 16:123.

40. Denning DW, Cadranel J, Beigelman-Aubry C, et al. Chronic pulmonary

aspergillosis – Rationale and clinical guidelines for diagnosis and management.

Eur Resp J 2016; 47:45-68.

41. Patterson TF, Thompson GW, Denning DW, et al. Practice guidelines for

the diagnosis and management of aspergillosis: 2015 Update by the Infectious

Diseases Society of America. Clin Infect Dis 2016 63:e1-e60.

42. Page ID, Richardson MD, Denning DW. Comparative diagnostic

performance of six Aspergillus-specific IgG assays for the diagnosis of chronic

pulmonary aspergillosis. J Infect 2016;72:240-9.

43. Langridge P, Sheehan R, Denning DW. Microbial yield from physiotherapy

assisted sputum production in respiratory outpatients. BMC Pulm Med

2016;16:23.

44. Farid S, Mohammed S, Devbhandari M, et al. Surgery for chronic

pulmonary aspergillosis, risk stratification and recurrence - A National Centre's

experience. J Cardiothorac Surg 2013; 8:180.

45. Al-shair K, Atherton GTW, Harris C, Ratcliffe L, Newton P, Denning DW.

Long-term antifungal treatment improves health status in patients with chronic

pulmonary aspergillosis; a longitudinal analysis. Clin Infect Dis 2013;57:828-35.

46. Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for

the management of patients with histoplasmosis: 2007 update by the Infectious

Diseases Society of America. Clin Infect Dis 2007;45:807-25.

47. Limper AH, Knox KS, Sarosi GA et al. An official American Thoracic Society

statement: Treatment of fungal infections in adult pulmonary and critical care

patients. Am J Respir Crit Care Med 2011;183:96-128.

48. Galgiani JN, Ampel NM, Blair JE, Catanzaro A, Johnson RH, Stevens DA,

Williams PL; Infectious Diseases Society of America. Coccidioidomycosis. Clin

Infect Dis 2005;41:1217-23.

49. Ampel NM, Giblin A, Mourani JP, Galgiani JN. Factors and outcomes

associated with the decision to treat primary pulmonary coccidioidomycosis.

Clin Infect Dis 2009;48:172-8.

21

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

50. Stockamp NW, Thompson GR 3rd. Coccidioidomycosis. Infect Dis Clin

North Am 2016;30:229-46.

51. Ferreira MS. Paracoccidioidomycosis. Paediatr Respir Rev 2009;10:161-5.

52. Borges SR, Silva GM, Chambela Mda C, et al. Itraconazole vs.

trimethoprim-sulfamethoxazole: A comparative cohort study of 200 patients

with paracoccidioidomycosis. Med Mycol 2014;52:303-10.

53. Castillo CG, Kauffman CA, Miceli MH. Blastomycosis. Infect Dis Clin North

Am 2016;30:247-64.

54. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for

the management of cryptococcal disease: 2010 update by the Infectious Diseases

Society of America. Clin Infect Dis 2010;50:291-322.

55. Denning DW, Pashley C, Hartl D, et al. Fungal allergy in asthma-state of the

art and research needs. Clin Transl Allergy 2014;4:14.

56. Moss RB. Treatment options in severe fungal asthma and allergic

bronchopulmonary aspergillosis. Eur Respir J. 2014;43:1487-500.

57. Chrdle A, Mustakim S, Bright-Thomas R, Baxter C, Felton T, Denning DW.

Aspergillus bronchitis in non-immunocompromised patients – case series,

response to treatment and criteria for diagnosis. NY Acad Sci 2012; 1272:73-85.

58. McKinsey DS, McKinsey JP. Pulmonary histoplasmosis. Semin Respir Crit

Care Med 2011;32:735-44.

59. Richer SM, Smedema ML, Durkin MM, et al. Improved diagnosis of acute

pulmonary histoplasmosis by combining antigen and antibody detection. Clin

Infect Dis. 2016 Apr 1;62(7):896-902.

60. Corzo-León DE, Armstrong-James D, Denning DW. Burden of serious

fungal infections in Mexico. Mycoses, 2015: 58 (Suppl. S5):34–44.

61. Goodwin RA Jr, Owens FT, Snell JD, et al. Chronic pulmonary

histoplasmosis. Medicine (Baltimore) 1976;55:413-52.

62. Hage CA, Ribes JA, Wengenack NL, et al. A multicenter evaluation of tests

for diagnosis of histoplasmosis. Clin Infect Dis 2011;53:448-54.

63. Jude CM, Nayak NB, Patel MK, Deshmukh M, Batra P. Pulmonary

coccidioidomycosis: pictorial review of chest radiographic and CT findings.

Radiographics 2014;34:912-25.

22

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

64. Malo J, Luraschi-Monjagatta C, Wolk DM, Thompson R, Hage CA, Knox KS.

Update on the diagnosis of pulmonary coccidioidomycosis. Ann Am Thorac Soc

2014;11:243-53.

65. Giacomazzi J, Baethgen L, Carneiro LC, et al. The burden of serious human

fungal infections in Brazil. Mycoses 2016;59:145-50.

66. Xie X, Xu B, Yu C, et al. Clinical analysis of pulmonary cryptococcosis in

non-HIV patients in south China. Int J Clin Exp Med 2015;8:3114-9.

67. Aberg JA, Mundy LM, Powderly WG. Pulmonary cryptococcosis in patients

without HIV infection. Chest 1999;115:734–740.

68. Quansah R, Jaakkola MS, Hugg TT, Heikkinen SA, Jaakkola JJ. Residential

dampness and molds and the risk of developing asthma: a systematic review and

meta-analysis. PLoS One 2012;7:e47526.

69. Denning DW, O'Driscoll BR, Hogaboam CM, Bowyer P, Niven RM. The link

between fungi and severe asthma: a summary of the evidence. Eur Respir J

2006;27:615-626.

70. O’Driscoll BR, Hopkinson LC, Denning DW. Mould sensitisation is common

amongst patients with severe asthma requiring multiple hospital admissions in

North West England. BMC Pulm Med 2005; 5:4.

71. Woolnough K, Fairs A, Pashley CH, Wardlaw AJ. Allergic fungal airway

disease: pathophysiologic and diagnostic considerations. Curr Opin Pulm Med

2015;21:39-47.

72. Agarwal R, Chakrabarti A, Shah A, et al. Allergic bronchopulmonary

aspergillosis: review of literature and proposal of new diagnostic and

classification criteria. Clin Exp Allergy 2013;43(8):850-873.

73. Packe GE, Ayres JG. Asthma outbreak during a thunderstorm. Lancet

1985;2:199-204.

74. Dales RE, Cakmak S, Judek S, et al. The role of fungal spores in

thunderstorm asthma. Chest. 2003;123:745-50.

75. Hayes JP, Rooney J. The prevalence of respiratory symptoms among

mushroom workers in Ireland. Occup Med (Lond) 2014;64:533-8.

76. Young RC, Bennett JE, Vogel CL, Carbone PP, DeVita VT. Aspergillosis. The

spectrum of the disease in 98 patients. Medicine (Baltimore). 1970;49:147-73.

23

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

77. Armstead J, Morris J, Denning DW. Multi-country estimate of different

manifestations of aspergillosis in cystic fibrosis. PLoS One 2014;9:e98502.

78. Moss RB. Fungi in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Semin Respir Crit Care Med 2015;36:207-16.

79. Amin R, Dupuis A, Aaron SD, Ratjen F. The effect of chronic infection with

Aspergillus fumigatus on lung function and hospitalization in patients with cystic

fibrosis. Chest. 2010;137:171-6.

80. Baxter CG, Dunn G, Jones AM, et al. Novel immunologic classification of

aspergillosis in adult cystic fibrosis. J Allergy Clin Immunol 2013; 132:560-566.

81. Pickering CA. Building sickness syndrome. Respir Med 1989;83:91-2.

82. Niven RM, Fletcher AM, Pickering CA, et al. Building sickness syndrome in

healthy and unhealthy buildings: an epidemiological and environmental

assessment with cluster analysis. Occup Environ Med 2000;57:627-34.

83. Ishibashi M, Tonori H, Miki T, et al. Classification of patients complaining

of sick house syndrome and/or multiple chemical sensitivity. Tohoku J Exp Med

2007;211:223-33.

84. Joshi SM. The sick building syndrome. Indian J Occup Environ Med.

2008;12:61-4.

85. Dantoft TM, Andersson L, Nordin S, Skovbjerg S. Chemical intolerance.

Curr Rheumatol Rev 2015;11:167-84.

86. Lago Blanco E, Puiguriguer Ferrando J, Rodríguez Enríquez M, Agüero

Gento L, Salvà Coll J, Pizà Portell MR. Multiple chemical sensitivity: Clinical

evaluation of the severity and psychopathological profile. Med Clin (Barc)

2016;146:108-11.

87. Miller CS, Prihoda TJ. The Environmental Exposure and Sensitivity

Inventory (EESI): a standardized approach for measuring chemical intolerances

for research and clinical applications. Toxicol Ind Health 1999;15:370-85.

88. Hauge CR, Rasmussen A, Piet J, et al. Mindfulness-based cognitive therapy

(MBCT) for multiple chemical sensitivity (MCS): Results from a randomized

controlled trial with 1 year follow-up. J Psychosom Res 2015;79:628-34.

89. Jacobs RL, Andrews CP, Coalson JJ. Hypersensitivity pneumonitis: beyond

classic occupational disease-changing concepts of diagnosis and management.

Ann Allergy Asthma Immunol 2005;95:115-28.

24

1

2

3

4

5

6

7

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25

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28

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30

31

32

33

90. Fink JN, Ortega HG, Reynolds HY, et al. Needs and opportunities for

research in hypersensitivity pneumonitis. Am J Respir Crit Care Med

2005;171:792-8.

91. Topping MD, Scarisbrick DA, Luczynska CM, Clarke EC, Seaton A. Clinical

and immunological reactions to Aspergillus niger among workers at a

biotechnology plant. Br J Ind Med 1985;42:312-8.

92. Blyth W, Grant IW, Blackadder ES, Greenberg M. Fungal antigens as a

source of sensitization and respiratory disease in Scottish maltworkers. Clin

Allergy 1977;7:549-62.

93. Huuskonen MS, Husman K, Järvisalo J, et al. Extrinsic allergic alveolitis in

the tobacco industry. Br J Ind Med 1984;41:77-83.

94. Wiszniewska M, Tymoszuk D, Nowakowska-Świrta E, Pałczyński C,

Walusiak-Skorupa J. Mould sensitisation among bakers and farmers with work-

related respiratory symptoms. Ind Health 2013;51:275-84.

95. Hinojosa M. Stipatosis or hypersensitivity pneumonitis caused by esparto

(Stipa tenacissima) fibers. J Investig Allergol Clin Immunol 2001;11:67-72.

96. Sabino R, Faísca VM, Carolino E, Veríssimo C, Viegas C. Occupational

exposure to Aspergillus by swine and poultry farm workers in Portugal. J Toxicol

Environ Health A 2012;75:1381-91.

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Figure legends

Figure 1 Spectrum of underlying disease and pulmonary mycoses. Aspergillosis

affects a broad spectrum of patients. Aspergillosis and cryptococcosis occur

worldwide, whereas endemic mycoses are geographically restricted.

Figure 2 CT scan showing moderate emphysema and a thin-walled right upper

lobe cavity containing intra-cavitary material and irregular wall laterally, with

pleural thickening. High titre A. fumigatus IgG antibodies were found.

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Table 1 Underlying conditions for chronic pulmonary aspergillosis37

Underlying condition

Frequency in series

Comment

Tuberculosis 17-80% Highest frequency probably soon after TB treatment is completed, but risk to persist for decades. Also seen in HIV positive patients

Emphysema/COPD 30-50% Bullous emphysema probably a key risk. Corticosteroids for exacerbations another risk

Non-tuberculous mycobacterial infection

<20% NTM may precede, be concurrent or follow CPA. Outcome determined by CPA not NTM

Pneumothorax or bullous lung disease

9-20% Often years before, but pleurectomy or talc pleurodesis also common history

ABPA and asthma 12-18% Radiological appearance of CPA in ABPA may differ with pleural fibrosis more common and cavities less common. Frequent corticosteroid courses may be a risk factor

Pulmonary fibrocystic sarcoidosis

9-17% Difficult to diagnose until aspergilloma apparent radiologically

Lung irradiation ~5%

Rheumatoid arthritis 2-4% May be Aspergillus-infected rheumatoid nodules

Ankylosing spondylitis

<5% Often isolated apical disease but very challenging surgically

COPD = chronic obstructive pulmonary disease, NTM = non-tuberculous

mycobacterial disease, CPA = chronic pulmonary aspergillosis, ABPA = allergic

bronchopulmonary aspergillosis

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Table 2

Differential diagnosis of a non-malignant pulmonary nodule – these differ by

geographical area. Exclusion of malignancy is important and can be impossible

without biopsy.

Cause of nodule/disease CT appearance

Coccidioidal nodule Usually single and in an upper lobe.

Occasionally calcified.

Aspergillus nodule Single or multiple. Any lobe may be

affected - upper lobes most common.

Occasionally calcified

Cryptococcal nodule Usually large and peripheral, single or

multiple and rarely cavitate or calcify.

Histoplasma nodule Single or multiple, small. Often calcified.

Non-tuberculous

mycobacterial nodule

Single or multiple. May be calcified.

Pneumocystis jirovecii Rare. Usually single but may be multiple,

usually immunocompromised

Nocardia spp. Single or multiple, usually

immunocompromised

Dirofilariasis ‘Coin lesion’. May be single or multiple

and may cavitate

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Table 3. Therapies for pulmonary fungal disease in non-immunocompromised patients

Pulmonary fungal disease Initial therapy Duration

(months)

Alternative therapy# Cautions References

Chronic pulmonary aspergillosis

Simple aspergilloma Surgical

resection

- None Sufficient respiratory

reserve, relapse possible40,41

Aspergillus nodule None if

asymptomatic

- Azole therapy if

progressive

If multiple, continued

imaging and possibly re-

biopsy, if progressive

39,40

Chronic cavitary and fibrosing Itraconazole or

voriconazole

>6, typically

long term

Posaconazole,

liposomal AmB (~3

mg/Kg), micafungin

Drug interactions,

especially rifampicin. Long

term toxicity - peripheral

neuropathy and skin

photosensitivity

(voriconazole)

40,41,45

Histoplasmosis

Acute pulmonary None,

Liposomal 1

None 46,47

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amphotericin B,

itraconazole 2-3

Chronic cavitary Itraconazole 12-24 Posaconazole 46

Coccidioidomycosis

Primary pulmonary None 2 Fluconazole,

itraconazole

Not of proven value, but

may be helpful in severe

cases, no impact on relapse

48,49

Coccidioidomycosis nodule None - 48

Chronic pulmonary Fluconazole,

itraconazole

12 Posaconazole,

liposomal AmB

Relapse rate ~50%48,50

Paracoccidioidomycosis

Juvenile Itraconazole 3-6 Liposomal AmB 51

Chronic pulmonary Itraconazole 6 Liposomal AmB 51,52

Blastomycosis None or

itraconazole

2-6 Liposomal AmB if very

unwell53

Cryptococcal pneumonia Fluconazole 6-12 Itraconazole or

voriconazole

Asymptomatic colonization

does not require therapy54

‘Fungal asthma’* Itraconazole 4-8 Nebulized AmB,

voriconazole,

Relapse rate ~50% 55,56

30

posaconazole

Aspergillus bronchitis Itraconazole 4 voriconazole,

posaconazole

Relapse rate ~50%57

* includes allergic bronchopulmonary aspergillosis (ABPA), severe asthma with fungal sensitization (SAFS).

AmB = amphotericin B,

# Careful monitoring of azole serum concentrations and possible toxicities and avoidance of drug interactions is recommended.

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